The psychotropic compound with which the present invention is concerned has the following structural formula: ##STR1## and is known as buspirone. The hydrochloride salt has been referred to in the prior art as MJ 9022-1 and as buspirone hydrochloride. Other acid addition salts thereof are named by combining "buspirone" with the appropriate word to define the acid from which it is prepared as in "buspirone hydrochloride". The latter is the United States Adopted Name (USAN); refer to J. American Med. Assoc. 225, 520 (1973). Buspirone is currently approved for marketing as an effective clinical anti-anxiety agent.
The synthesis of the compound and the disclosure of its psychotropic properties are described in the following representative patents and publications.
1. Y. H. Wu. et al., J. Med. Chem., 15.477 (1972). PA1 2. Y. H. Wu, et al., U.S. Pat. No. 3,717,634 which issued Feb. 20, 1973. PA1 3. L. E. Allen et al., Arzneium. Forsch., 24. No. 6 917-922 (1974). PA1 4. G. L. Sathananthan, et al., Current Therapeutic Research. 18/5, 701-705 (1975). PA1 5. Y. H. Wu. et al., U.S. Pat. No. 3,976,776, issued Aug. 24, 1976. PA1 6. J. C. Simms. U.S. Pat. No. 4,351,939, issued Sept. 28, 1982. PA1 (a) disrupting the crystalline structure of either one or a mixture of the two starting polymorphic forms of buspirone hydrochloride; and PA1 (b) allowing recrystallization to occur under equilibrium conditions at a temperature either higher than about 95.degree. C. if the higher melting polymorphic crystalline form of buspirone hydrochloride is desired, or under equilibrium conditions at temperatures lower than about 95.degree. C. if the lower melting polymorphic crystalline form of buspirone hydrochloride is desired. PA1 (a) disrupting the crystal structure of solid buspirone hydrochloride by dissolution by the liquid medium: PA1 (b) allowing recrystallization to occur in a selected temperature range, either above or below 95.degree. C.: PA1 (c) agitating the solid buspirone hydrochloride: liquid medium mixture for a time sufficient to obtain solid/solution equilibrium in the mixture; and PA1 (d) separating the desired crystalline polymorph from the liquid component of the mixture. PA1 (a) disrupting the crystal structure of solid buspirone hydrochloride by dissolution in a suitable liquid medium; PA1 (b) allowing recrystallization to occur while the temperature is kept below about 95.degree. C.; PA1 (c) while maintaining the temperature below about 95.degree. C., the solid buspirone hydrochloride: liquid medium mixture is agitated for a period of time sufficient to obtain solid/solution equilibrium; and PA1 (d) separating the desired low-melting polymorph from the liquid component of the mixture. PA1 (a) disrupting the crystal structure of solid buspirone hydrochloride by dissolution in a suitable liquid medium; PA1 (b) allowing recrystallization to occur while the temperature is kept above about 95.degree. C.; PA1 (c) while maintaining the temperature above about 95.degree. C., the solid buspirone hydrochloride: liquid medium mixture is agitated for a period of time sufficient to obtain solid/solution equilibrium; and PA1 (d) separating the desired high-melting polymorph from the liquid component of the mixture.
The melting point disclosed for buspirone hydrochloride in the above-listed references is 201.5.degree. to 202.5.degree. C. No other melting point values outside a range of 201.degree. to 205.degree. for pure buspirone hydrochloride has been previously disclosed. As one aspect of the instant invention it has been discovered that solid buspirone hydrochloride can exist in two different crystalline phases. The capacity to occur in different crystal structures is known as polymorphism and is known to occur in many organic compounds including drugs. These different crystalline forms are known as "polymorphic modifications" or "polymorphs" and are realized only in the crystalline state. While polymorphic modifications have the same chemical composition, they differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. As such, these modifications may have different solid-state physical properties such as shape, color, density, harness, deformability, stability, dissolution properties, and the like. Polymorphism of an organic drug molecule and its consequences would be appreciated by one skilled in the pharmaceutical arts.
As an example; Gordon, et al. in U.S. Pat. No. 4,476,248, issued Oct. 7, 1984, disclosed and claimed a new crystalline form of the drug ibuprofen as well as the process for producing it. The new crystalline form was reported to improve the manufacturability of ibuprofen.
In the manufacture of pharmaceutical supplies of buspirone hydrochloride, certain specified criteria, such as the melting point for example, defining physical characterization and purity of the pure drug substance must be met before it can be incorporated into pharmaceutical compositions for medicinal purposes. Satisfying these criteria is one requirement of the approvability process allowing continued distribution of drug product under good manufacturing procedure guidelines and regulations set forth by governmental agencies such as the Food and Drug Agency (FDA) in the U.S. Compliance with governmental regulations for drug manufacture requires meeting the requisite drug substance specifications as well as keeping related records and other quality assurance procedures for each batch of drug substance to be put into the pharmaceutical product manufacturing process. These requirements are required of every drug manufacturer for every drug falling under purview of the FDA or other appropriate governmental drug agency.
In the course of preparing larger batch lots of buspirone hydrochloride, a problem was experienced in meeting the specified melting point criterion. Closer examination led to the unexpected discovery of a second polymorphic modification of buspirone hydrochloride. This second polymorphic modification displays a melting point of about 188.degree. as compared with the melting point of about 202.degree. to 204.degree. for the originally discovered polymorphic form. Since the extensive, expensive and time-consuming clinical studies required for drug approval were done with the original polymorph (designated P203), the specifications for drug substance are for this polymorph in the approved New Drug Application (NDA) of buspirone. However, increasing difficulty was experienced in continued preparation of P203 and, to add further complication, some batches of P203 underwent partial conversion to P188 during storage.
It is therefore an object of this invention to be able to reliably provide a crystalline form of buspirone hydrochloride which can be produced, stored, and compounded while continuing to meet its required specifications for a pure drug substance. It is a further object of this invention to provide a reliable process whereby whichever polymorphic form desired, P188 or P203, can be conveniently and reproducibly prepared.
Other objects, aspects and advantages of this invention will become apparent from reading the remaining specification and the claims which follow.